Aashish Manglik

Mapping the sequence determinants of constitutive activity in GPCRs

The paper measures basal activity across the human GPCR family on a single scale and identifies key residues that influence constitutive signaling.

Distinct activation mechanisms underlie ligand efficacy at a GPCR

This study uses deep mutational pharmacology to show how different residues in the -opioid receptor determine the efficacy of opioids by shaping distinct activation mechanisms.

Programming Targeted Immune Cell Migration Using Orthogonal Chemokine-Receptor Pairs

This study engineers orthogonal chemokine-receptor pairs to enable targeted immune cell migration and collective swarming behavior in engineered T cells.

Allosteric Gating Mechanism Regulates Odorant Selectivity and Antagonism in Odorant Receptors

This study investigates how odorant receptors regulate selectivity and antagonism through allosteric gating mechanisms using simulations and experiments.

Toward a Random Background for Ligand Optimization

This study systematically evaluates the effectiveness of random small perturbations in ligand optimization, finding 11.2% of analogs improved potency by ≥10-fold but often had worse pharmacokinetics.

An engineered nanobody inhibitor for molecular-to-circuit control of opioid receptor function

This paper develops an engineered nanobody inhibitor to control opioid receptor function with subcellular precision and demonstrates its effectiveness in vivo.

Atypical GPCR Activation Resolved by Nanobody Engineering

This study reveals an unconventional activation mechanism of the atypical GPCR ACKR3 using engineered nanobodies and cryo-EM, showing that extracellular pocket volume changes, not microswitch conformational shifts, drive receptor activity.

Deep Receptor Scanning Reveals General Sequence Constraints on GPCR Biosynthesis

The paper introduces a platform to characterize GPCR expression and uses machine learning to identify structural features affecting their biosynthesis.

Phenotypic pleiotropy of missense variants in human B cell-confinement receptor P2RY8

The paper uses deep mutational scanning and structural analysis to study the functional effects of missense variants in the P2RY8 receptor and improves variant effect predictions.

Docking 14 million virtual isoquinuclidines against the mu and kappa opioid receptors reveals dual antagonists-inverse agonists with reduced withdrawal effects

The paper screens 14.6 million virtual isoquinuclidines against opioid receptors to identify dual antagonists-inverse agonists with reduced withdrawal effects compared to naloxone.

Molecular basis of proton-sensing by G protein-coupled receptors

The paper identifies proton-sensing mechanisms in GPCRs using cryo-EM and deep mutational scanning, revealing a network of residues rather than a single site for proton recognition.

Structural Basis of μ-Opioid Receptor-Targeting by a Nanobody Antagonist

This paper describes a nanobody antagonist of the μ-opioid receptor, revealing its structural basis and designing peptide analogues with antagonistic activity.

Engineered odorant receptors illuminate structural principles of odor discrimination

The paper uses engineered odorant receptors to uncover structural principles of odor discrimination by solving cryoEM structures of consensus ORs and comparing their ligand recognition properties.

Protein Design and Variant Prediction Using Autoregressive Generative Models

This paper introduces an alignment-free deep generative model for protein design and variant effect prediction, showing improved performance over existing methods in challenging cases.

A genetically encoded biosensor reveals location bias of opioid drug action

This study develops a biosensor to map opioid receptor activation in neurons, showing drugs activate receptors in the Golgi and dendrites, while peptides activate them in the plasma membrane and endosomes.